Although small interfering RNAs (siRNAs) hold promise as nucleic acid-based therapeutics, effective and well-controlled in vivo delivery remains challenging for two main reasons. First, crossing biological barriers such as the stratum corneum (for skin delivery), the cell membrane, and the endosomal compartment is difficult. Second, long-term therapeutic effects will require repeated dosing. We already know that unmodified siRNA molecules are not taken up efficiently by most cells owing to their size (˜13,000 Mw) and anionic nature, and therefore may not result in effective gene silencing in vivo. Nanoparticles have the potential for meeting both challenges. Utilization of nanoparticles engineered for slow, sustained and controlled release of functional siRNA may decrease the frequency of treatment and lead to more effective therapies. To overcome the previously mentioned delivery challenges, lipid-based delivery systems, such as cationic liposomes and stable nucleic acid-lipid particle (SNALP), have been employed to mask the negative charges on the siRNA phosphodiester backbone and facilitate uptake. Building on this theme, other delivery vehicles based on the variety of cationic and biodegradable polymers have been developed, but many proposed approaches have demonstrated limited delivery of siRNA. Thus, other approaches are needed.